Two regioisomeric series of diaryl 2- or 4-amidopyrimidines have been synthesized and their adenosine receptor affinities were determined in radioligand binding assays at the four human adenosine receptors (hARs). Some of the ligands prepared herein exhibit remarkable affinities (K(i) < 10 nm) and, most noticeably, the absence of activity at the A(1), A(2A), and A(2B) receptors. The structural determinants that support the affinity and selectivity profiles of the series were highlighted through an integrated computational approach, combining a 3D-QSAR model built on the second generation of GRid INdependent Descriptors (GRIND2) with a novel homology model of the hA(3) receptor. The robustness of the computational model was subsequently evaluated by the design of new derivatives exploring the alkyl substituent of the exocyclic amide group. The synthesis and evaluation of the novel compounds validated the predictive power of the model, exhibiting excellent agreement between predicted and experimental activities.

We report the identification of two subsets of fluorinated nonxanthine A2B adenosine receptor antagonists. The novel derivatives explore the effect of fluorination at different positions of two pyrimidine-based scaffolds. The most interesting ligands combine excellent hA2B affinity (K i < 15 nM) and remarkable subtype selectivity. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The compounds were designed on the basis of previous molecular models of the stereoselective binding of the parent scaffolds to the hA2B receptor, and we herein provide refinement of such models with the fluorinated compounds, which allows the explanation of the spurious effects of the fluorination at the different positions explored. These models are importantly confirmed by a synergistic study combining chiral HPLC, circular dichroism, diastereoselective synthesis, molecular modeling, and X-ray crystallography, providing experimental evidence toward the stereospecific interaction between optimized trifluorinated stereoisomers and the hA2B receptor.

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A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A 2B AR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4dihydrobenzo [4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (K i < 30 nM) and exquisite selectivity. The structure−activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA 2B AR and the eutomer of the most attractive novel antagonist (S)-18g (K i = 3.66 nM) was validated.

Many drugs with very different affinity to a large number of receptors are described. Thus, in this work, we selected drug-target pairs (DTPs/nDTPs) of drugs with high affinity/nonaffinity for different targets. Quantitative structure-activity relationship (QSAR) models become a very useful tool in this context because they substantially reduce time and resource-consuming experiments. Unfortunately, most QSAR models predict activity against only one protein target and/or they have not been implemented on a public Web server yet, freely available online to the scientific community. To solve this problem, we developed a multitarget QSAR (mt-QSAR) classifier combining the MARCH-INSIDE software for the calculation of the structural parameters of drug and target with the linear discriminant analysis (LDA) method in order to seek the best model. The accuracy of the best LDA model was 94.4% (3,859/4,086 cases) for training and 94.9% (1,909/2,012 cases) for the external validation series. In addition, we implemented the model into the Web portal Bio-AIMS as an online server entitled MARCH-INSIDE Nested Drug-Bank Exploration & Screening Tool (MIND-BEST), located at http://miaja.tic.udc.es/Bio-AIMS/MIND-BEST.php . This online tool is based on PHP/HTML/Python and MARCH-INSIDE routines. Finally, we illustrated two practical uses of this server with two different experiments. In experiment 1, we report for the first time a MIND-BEST prediction, synthesis, characterization, and MAO-A and MAO-B pharmacological assay of eight rasagiline derivatives, promising for anti-Parkinson drug design. In experiment 2, we report sampling, parasite culture, sample preparation, 2-DE, MALDI-TOF and -TOF/TOF MS, MASCOT search, 3D structure modeling with LOMETS, and MIND-BEST prediction for different peptides as new protein of the found in the proteome of the bird parasite Trichomonas gallinae, which is promising for antiparasite drug targets discovery.